Amide inhibitors of leukotriene A4 hydrolase

1 . A compound of formula (I):

wherein:

R is

i) the group

ii) the group

iii) an optionally substituted heteroaryl;

n 1 , n 2 , and n 3 are each independently 0 to 2;

r is 0 to 4;

q is 0 to 2;

R 1a , R 1b , R 1c , R 1d and R 1e are each independently selected from hydrogen, —R 14 —OR 11 , —R 14 —C(═O)OR 11 , —R 14 —C(═O)R 11 , alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

or R 1a and R 1d , together with the carbons to which they are attached, form an optionally substituted heteroaryl or optionally substituted heterocyclyl;

R 1v , R 1w , R 1x , R 1y and R 1z are each independently hydrogen or fluoro;

R 2 is hydrogen, —R 13 —OR 11 , —R 13 —N(R 11 )R 12 , —R 14 —C(═O)OR 11 , —R 14 —C(═O)N(R 11 )R 12 , alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

or R 2 and R 7 , together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

or R 2 and R 7 , together with the nitrogens to which they are attached and one of R 5 , R 5b and R 5c , form an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

or R 2 and R 5 , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

or R 2 and R 5b , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

or R 2 and R 5c , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

or R 2 and R 8 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;

R 4a , R 4b and R 4c are each independently a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;

each R 5a , R 5b , R 5c , R 6a , R 6b and R 6c is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

or R 5a and R 5b , together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl;

or R 5b and R 6b , together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl;

or R 5a and R 6a together, R 5b and R 6b together, or R 5c and R 6c together may form an oxo;

R 7 is hydrogen, —R 13 —OR 11 , —R 14 —C(═O)R 11 , —R 14 —C(═O)OR 11 , —R 14 —C(═O)—R 14 —N(R 11 )R 12 , —R 13 —N(R 11 )C(═O)N(R 11 )R 12 , alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl;

or R 7 and R 5a , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

or R 7 and R 5b , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

or R 7 and R 5c , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

R 8 is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 13 —OR 10 , —R 13 —O—R 14 —C(═O)OR 10 , —R 13 —C(═O)R 10 , —R 13 —C(═O)OR 10 , —R 13 —C(═O)—R 14 —C(═O)OR 10 , —R 13 —C(═O)—R 13 —N(R 10 )R 11 , —R 13 —C(═O)—R 14 —S(═O) t N(R 10 )R 11 (where t is 1 or 2), or —R 14 —S(═O) p R 10 (where p is 0, 1 or 2);

or R 8 is aralkyl optionally substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, optionally substituted heteroaryl, hydroxyiminoalkyl, —R 13 —OR 10 , —R 13 —C(═O)R 10 , —R 13 —C(═O)OR 10 , —R 13 —C(═O)—R 13 —N(R 10 )R 11 , —R 13 —C(═O)N(R 10 )—R 14 —N(R 10 )R 11 , —R 13 —S(═O) t N(R 10 )R 11 (where t is 1 or 2), —R 13 —N(R 10 )R 11 , —R 13 —N(R 10 )C(═O)R 10 , —R 13 —N(R 10 )C(═O)—R 113 —N(R 10 )R 11 , —R 13 —N(R 10 )—R 13 —C(═O)OR 10 , —R 13 —N(R 10 )C(═O)—R 14 —S(═O) t N(R 10 )R 11 (where t is 1 or 2), —R 13 —N(R 10 )C(═O)—R 13 —N(R 10 )C(═O)R 10 , —R 13 —N(R 10 )C(═O)—R 13 —N(R 10 )—R 14 —N(R 10 )R 11 , —R 13 —N(R 10 )S(═O) t N(R 10 )R 11 (where t is 1 or 2), and —R 13 —O—R 14 —C(═O)OR 10 ;

each R 9 is independently —O—R 10 , alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl;

each R 10 and R 11 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

or R 10 and R 11 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

R 12 is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;

R 12a is an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;

each R 13 is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and

each R 14 is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain;

as a single stereoisomer or as a mixture of stereoisomers;

or a pharmaceutically acceptable salt, solvate, polymorph, clathrate, ammonium ion, N-oxide or prodrug thereof.

2 . A compound according to claim 1 wherein R is the group

3 . A compound according to claim 2 wherein

R 1a is hydrogen, —R 13 —C(O)OR 10 , —R 13 —C(O)R 10 , alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and

R 1b , R 1c , R 1d and R 1e are each independently hydrogen or halo.

4 . A compound according to claim 2 wherein

R 1a is hydrogen, —R 13 —C(O)OR 10 , —R 13 —C(O)R 10 , alkyl, halo, haloalkyl, optionally substituted phenyl, furanyl, thienyl, thiazolyl, or optionally substituted oxazolyl; and

R 1b , R 1c , R 1d and R 1e are each hydrogen.

5 . A compound according to claim 1 wherein R is the group

6 . A compound according to claim 1 wherein R an optionally substituted heteroaryl.

7 . A compound according to claim 6 wherein R is furanyl, oxazolyl, pyrazolyl, pyridinyl, triazolyl, thiazolyl, or benzothiazolyl, each of which is optionally substituted.

8 . A compound according to claim 1 wherein:

R 2 is hydrogen, —R 13 —OR 11 , —R 13 —N(R 11 )R 12 , —R 14 —C(═O)OR 11 , —R 14 —C(═O)N(R 11 )R 12 , alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl;

or R 2 and R 8 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

R 7 is selected from the group consisting of hydrogen, —RO 3 —OR 11 , —R 14 —C(═O)R 11 , —R 14 —C(═O)OR 11 , —R 14 —C(═O)—R 14 —N(R 11 )R 12 , —R 13 —N(R 11 )C(═O)N(R 11 )R 12 , alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl;

R 8 is selected from the group consisting of hydrogen, —R 13 —OR 11 , —R 14 —C(═O)OR 11 , —R 14 —S(═O) p R 11 (where p is 0, 1 or 2), —R 14 —C(═O)R 12 , —R 14 —C(═O)N(R 11 )R 12 , —R 13 —O—R 14 —C(═O)OR 11 , alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; and

R 10 is selected from the group consisting of hydrogen and alkyl.

9 . A compound according to claim 8 wherein:

R 4a and R 4b are each a direct bond;

R 4c is a direct bond or an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

10 . A compound according to claim 9 wherein:

r is 0;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4c is a direct bond or an optionally substituted straight or branched alkylene chain;

R 5a , R 5b , R 5c , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

11 . A compound according to claim 9 wherein:

r is 0;

q is 0 to 2;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4c is a direct bond or an optionally substituted straight or branched alkylene chain;

R 5a and R 5b , together with the carbons to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl;

or R 5b and R 6b , together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

12 . A compound according to claim 1 wherein:

R 2 and R 7 , together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

or R 2 and R 7 , together with the nitrogens to which they are attached and one of R 5 , R 5b and R 5c , form an optionally substituted 6- to 10-membered bridged N-heterocyclyl; and

R 10 is selected from the group consisting of hydrogen and alkyl.

13 . A compound according to claim 12 wherein:

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4a , R 4b and R 4c are each a direct bond or an optionally substituted straight or branched alkylene chain;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

14 . A compound according to claim 13 wherein R 2 and R 7 , together with the nitrogens to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl.

15 . A compound according to claim 14 having the following formula (I-1):

wherein:

R 5a , R 5b , R 5c , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

or R 5a and R 6a together, R 5b and R 6b together, or R 5c and R 6c together may form an oxo.

16 . A compound according to claim 14 wherein R 2 and R 7 , together with the nitrogens to which they are attached, form an optionally substituted piperazinyl or an optionally substituted tetrahydropyrimidinyl.

17 . A compound according to claim 13 wherein R 2 and R 7 , together with the nitrogen to which they are attached and one of R 5a , R 5b and R 5c , form an optionally substituted 6- to 10-membered bridged N-heterocyclyl.

18 . A compound according to claim 17 having the following formula (I-2):

19 . A compound according to claim 1 wherein:

q is 1 to 2;

R 2 and R 5a , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4a , R 4b and R 4c are each a direct bond or an optionally substituted straight or branched alkylene chain;

R 5b , R 5c , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

R 10 is selected from the group consisting of hydrogen and alkyl;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

20 . A compound according to claim 1 wherein:

q is 1 to 2;

R 2 is hydrogen, —R 13 —OR 11 , —R 13 —N(R 12 )R 2 , —R 14 —C(═O)OR 11 , —R 14 —C(═O)N(R 11 )R 12 , alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl;

or R 2 and R 8 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4a , R 4b and R 4c are each a direct bond or an optionally substituted straight or branched alkylene chain;

R 5a , R 5b , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

R 7 and R 5c , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl or an optionally substituted 6- to 10-membered bridged N-heterocyclyl;

R 8 is selected from the group consisting of hydrogen, —R 13 —OR 11 , —R 14 —C(═O)OR 11 , —R 14 —S(═O) p R 11 (where p is 0, 1 or 2), —R 14 —C(═O)R 12 , —R 14 —C(═O)N(R 11 )R 12 , —R 13 —O—R 14 —C(═O)OR 11 , alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl;

R 10 is selected from the group consisting of hydrogen and alkyl;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

21 . A compound according to claim 1 wherein:

R 2 and R 5b , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4a , R 4b and R 4c are each a direct bond or an optionally substituted straight or branched alkylene chain;

R 5a , R 5c , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

22 . A compound according to claim 1 wherein:

R 2 is hydrogen, —RO 3 —OR 11 , —R 13 —N(R 11 )R 12 , —R 14 —C(═O)OR 11 , —R 14 —C(═O)N(R 11 )R 12 , alkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl;

or R 2 and R 8 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4a , R 4b and R 4c are each a direct bond or an optionally substituted straight or branched alkylene chain;

R 5a , R 5c , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

R 7 and R 5b , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

R 8 is selected from the group consisting of hydrogen, —R 13 —OR 11 , —R 14 —C(═O)OR 11 , —R 14 —S(═O) p R 11 (where p is 0, 1 or 2), —R 14 —C(═O)R 12 , —R 14 —C(═O)N(R 11 )R 12 , —R 13 —O—R 14 —C(═O)OR 11 , alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl;

R 10 is selected from the group consisting of hydrogen and alkyl;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

23 . A compound according to claim 1 wherein:

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4a , R 4b and R 4c are each a direct bond or an optionally substituted straight or branched alkylene chain;

R 5b , R 5c , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

R 7 and R 5a , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

R 10 is selected from the group consisting of hydrogen and alkyl;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

24 . A compound according to claim 1 wherein:

q is 1 to 2;

R 2 and R 5c , together with the nitrogen and carbon to which they are attached, form an optionally substituted 5- to 7-membered N-heterocyclyl;

R 3 is a direct bond, —O—, —R 13 —O—, —O—R 13 —, —O—R 13 —O—, or an optionally substituted straight or branched alkylene chain;

R 4a , R 4b and R 4c are each a direct bond or an optionally substituted straight or branched alkylene chain;

R 5a , R 5b , R 6a , R 6b and R 6c are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aralkyl or —R 14 —C(═O)OR 11 ;

R 10 is selected from the group consisting of hydrogen and alkyl;

each R 13 is an optionally substituted straight or branched alkylene chain; and

each R 14 is a direct bond or an optionally substituted straight or branched alkylene chain.

25 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 .

26 . A method of treating a disease or disorder ameliorated by the inhibition of LTA 4 -h activity in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of compound of claim 1 .

27 . The method according to claim 26 wherein the disease or disorder is selected from the group consisting of acute inflammation, chronic inflammation, anaphylactic reactions, allergic reactions, allergic contact dermatitis, allergic rhinitis, chemical and non-specific irritant contact dermatitis, urticaria, atopic dermatitis, psoriasis, fistulas associated with Crohn's disease, pouchitis, septic or endotoxic shock, hemorrhagic shock, shock-like syndromes, capillary leak syndromes induced by immunotherapy of cancer, acute respiratory distress syndrome, scleroderma lung disease, traumatic shock, immune- and pathogen-induced pneumonias, immune complex-mediated pulmonary injury and chronic obstructive pulmonary disease, inflammatory bowel diseases, ulcerative colitis, Crohn's disease, post-surgical trauma, gastrointestinal ulcers, diseases associated with ischemia-reperfusion injury, acute myocardial ischemia, infarction, acute renal failure, ischemic bowel disease, acute hemorrhagic or ischemic stroke, immune-complex-mediated glomerulonephritis, autoimmune diseases, insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, acute and chronic organ transplant rejection, transplant arteriosclerosis, transplant fibrosis, cardiovascular disorders, hypertension, atherosclerosis, aneurysm, critical leg ischemia, peripheral arterial occlusive disease, Reynaud's syndrome, diabetic nephropathy, neuropathy, retinopathy, macular degeneration, glaucoma, neurodegenerative disorders, delayed neurodegeneration in stroke, Alzheimer's disease, Parkinson's disease, encephalitis, HIV dementia, inflammatory pain, neuropathic pain, arthritic pain, periodontal disease, gingivitis, ear infections, migraine, benign prostatic hyperplasia, cancer, leukemias, lymphomas, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head tumors, neck tumors and colorectal cancer.